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Results for “Innate Immunity Recognition”

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PubMed2002

Discovery of immunostimulatory CpG-DNA and its application to tuberculosis vaccine development.

DNA containing an unmethylated CpG motif has a potent immunostimulatory effect on the vertebrate immune system. Because such CpG motifs are relatively common in bacterial DNA, but rare in mammalian animal and plant DNA, they may be an evolutionary adaptation augmenting innate immunity, most likely in response to pathogens that replicate within the host cells, such as viruses and intracellular bacteria. Microbial infection induces innate immunity by triggering pattern-recognition systems. The infected cells produce proinflammatory cytokines that directly combat microbial invaders and express costimulating surface molecules, which develop adaptive immunity by inducing distinct T cell differentiation. Bacterial DNA with unmethylated CpG-DNA stimulates vertebrate immature immune cells to induce maturation and to produce TNF-alpha as well as Th1-type cytokines, IL-12 and IFN-gamma. Therefore, CpG-DNA functions as an adjuvant for regulating the initiation of Th1 differentiation. The roles of immunostimulatory CpG motifs in DNA vaccine developments and in therapeutic applications have been discussed.

Adjuvants, Immunologic↗

PubMed2003

[The application of molecular biology to anti-endotoxin therapies].

Toll-like receptors (TLRs), recently identified on macrophages and dendritic cells in mammals, recognize a specific pattern of pathogen components, including endotoxins(lipopolysaccharide). Pathogen recognition by TLRs activates the innate immune system through the signaling pathway and provokes inflammatory responses, such as inducing the production of cytokines. Therefore the specific inhibition of the signaling pathway and the administration of excess inflammatory responses have useful potential in the management of sepsis syndrome. Currently, several monoclonal antibodies are applicable to the treatment of autoimmune diseases and cancer. On the other hand, immunotherapies against proinflammatory cytokines in septic shock have failed to demonstrate clinical benefit. In this review, we summarize recent views of novel therapeutic targets, provided from molecular biologic studies of gram-negative infection.

Animals↗

PubMed2004

CpG DNA as a potent inducer of mucosal immunity: implications for immunoprophylaxis and immunotherapy of mucosal infections.

Recent advances in immunology reveal that vertebrate innate immune systems use pattern-recognition receptors, of which the best characterized is the toll-like receptor (TLR) family, to specifically detect pathogen-associated molecular patterns (PAMPs) present in infectious agents. Based on this, use of synthetic PAMPs has attracted much interest for specific immunoprophylaxis and immunotherapy purposes. Among the PAMPs, immunostimulatory CpG DNA, a TLR9 ligand, displays promising potent immunostimulatory and adjuvanticity in different settings. In this review, recent developments in the use of CpG DNA for inducing immunity in the mucosal tissues will be highlighted.

Adjuvants, Immunologic↗

PubMedDate not supplied

The emerging functionality of endogenous lectins: A primer to the concept and a case study on galectins including medical implications.

Biochemistry textbooks commonly make it appear that it is a foregone conclusion that the hardware of biological information storage and transfer is confined to nucleotides and amino acids, the letters of the genetic code. However, the remarkable talents of a third class of biomolecules are often overlooked. For example, one of them far surpasses the building blocks of nucleic acids and proteins in terms of theoretical coding capacity by oligomer formation. Although often exclusively assigned to duties in energy metabolism, carbohydrates as part of cellular glycoconjugates (glycoproteins, proteoglycans, glycolipids) have, in fact, other important tasks. Currently, they are increasingly gaining recognition as an operative high-density information coding system. An elaborate enzymatic machinery enables cells to be versatile enough to produce a glycan profile (glycome) that is as characteristic as a fingerprint. Moreover, swift modifications during dynamic processes, such as differentiation or malignant transformation, are readily possible. The translation of the information presented in oligosaccharide determinants to biological responses is carried out by lectins. Recognition of foreign glycosignatures in innate immunity, regulation of cell-cell/matrix interactions, cell migration or growth, and intra- and intercellular glycan routing etc represent physiologically far-reaching lectin-carbohydrate functionality. The classification of endogenous lectins is guided by sequence alignments and conservation of distinct structural traits. For example, a jelly-roll-like folding pattern and maintenance of key residue positioning involved in stacking and C-H/pi-interactions as well as directional hydrogen bonds to the 1-galactoside ligands are common denominators among galectins. Biochemical and biophysical studies are beginning to unravel the intricacies of the selection of a limited set of endogenous ligands, such as certain integrins or ganglioside GM1, and combined with biological cell experiments, its relevance for cell sociology, e.g. in growth regulation and tumor cell invasion or activated T cell apoptosis. Histopathological monitoring accompanies the biological cell investigations, linking expression of certain family members to tumor progression or suppression. Further insights into the functional consequences of the sugar code's translation are thus expected to have notable repercussions for diagnostic and therapeutic procedures.

Amino Acid Sequence↗

PubMed2006

Masked oral prodrugs of toll-like receptor 7 agonists: a new approach for the treatment of infectious disease.

Toll-like receptor (TLR)7 is a pattern-recognition receptor that activates the innate immune response. Stimulation of TLR7 induces type I interferons, pro-inflammatory cytokines, the upregulation of co-stimulatory molecules and leads to the development of an adaptive immune response. Small-molecule TLR7 agonists with broad-spectrum antiviral activities in animal models have been identified. Such compounds have been examined clinically for a number of different infectious disease indications, leading to marketing approval of one of these agents, imiquimod, for the topical treatment of external genital and perianal papillomavirus infections. In contrast with topical and intravenous routes of administration, compounds delivered orally have exhibited poor tolerability at desired doses, with substantial adverse events associated with gastrointestinal toxicity. However, dosing with masked oral prodrugs of TLR7 agonists, such as ANA-975, limits the adverse events associated with the activation of responsive gastrointestinal immune tissue. As a consequence, the treatment of systemic diseases, such as chronic hepatitis C, can now be explored with orally administered TLR7 agonists.

Administration, Oral↗

PubMed2006

A novel 40-kDa protein containing six repeats of an epidermal growth factor-like domain functions as a pattern recognition protein for lipopolysaccharide.

Determination of structures and functions of pattern recognition proteins are important for understanding pathogen recognition mechanisms in host defense and for elucidating the activation mechanism of innate immune reactions. In this study, a novel 40-kDa protein, named LPS recognition protein (LRP), was purified to homogeneity from the cell-free plasma of larvae of the large beetle, Holotrichia diomphalia. LRP exhibited agglutinating activities on Escherichia coli, but not on Staphylococcus aureus and Candida albicans. This E. coli-agglutinating activity was preferentially inhibited by the rough-type LPS with a complete core oligosaccharide. LRP consists of 317 aa residues and six repeats of an epidermal growth factor-like domain. Recombinant LRP expressed in a baculovirus system also showed E. coli agglutination activity in vitro and was able to neutralize LPS by inhibition of LPS-induced IL-6 production in mouse bone marrow mast cells. Furthermore, E. coli coated with the purified LRP were more rapidly cleared in the Holotrichia larvae than only E. coli, indicating that this protein participates in the clearance of E. coli in vivo. The three amino-terminal epidermal growth factor-like domains of LRP, but not the three carboxyl epidermal growth factor-like domains, are involved in the LPS-binding activity. Taken together, this LRP functions as a pattern recognition protein for LPS and plays a role as an innate immune protein.

Agglutination↗

PubMed2002

Intracellular vs extracellular recognition of pathogens--common concepts in mammals and flies.

There are common themes in innate immune defense systems across the animal and plant kingdoms. Pathogen recognition is commonly based on the identification of microbial molecular patterns by defined receptors and the subsequent activation of signaling pathways that initiate a defense response to fend off the invading microorganism. The existence of mammalian Toll-like receptors (TLRs) and the recent identification of two mammalian nucleotide-binding site leucine-rich repeat (NBS-LRR) proteins (NOD1 and NOD2) as intracellular sensors of bacterial products bring new insights into the possibility of extracellular versus intracellular pathogen recognition and signal transduction depending on the nature of the infection. The homology between TLRs and the Toll system in Drosophila suggests that conserved defense mechanisms are likely to be shared by diverse organisms.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Toll-like receptors and NOD/CARD proteins: pattern recognition receptors are key elements in the regulation of immune response.

The magnitude of the response to a specific immunogen such as an infectious agent is the result of a complex interaction between genetic and environmental factors. For example, in intestinal inflammation, the inflammatory response appears to be regulated by the indigenous microflora of the gut, by receptors in epithelial cells and antigen-presenting cells in the intestinal mucosa, and by immunologic factors. Recent evidence suggests that genetic variants of human immunomodulating genes influence the susceptibility to and severity of infectious diseases and the subsequent clinical outcome of disease. This review will focus on recently identified pattern recognition receptors which are located on innate immune and epithelial cells, and recognize pathogen-associated molecular patterns. The binding of specific pathogen-associated molecular patterns to these receptors results in the activation of a signal transduction pathway through nuclear factor (NF)-kappaB which leads to either enhanced or inhibited immune responses that modify the production of inflammatory effectors, such as cytokines. This article reports on the identification and functional characterization including the discovery of mutants which completely abolish NF-kappaB signal transduction of pattern recognition receptors, such as the extracellular Toll-like receptors and the intracellular nucleotide oligomerization domain/caspase recruitment domain (NOD/CARD) receptors, as well as their role in clinical disease. Knowledge of pattern recognition receptors such as Toll-like receptors and NOD/CARD intracytoplasmic proteins, including their functions and their downstream signaling pathways, may provide a new molecular basis for preventing or blocking inflammation associated with pathogenic microorganisms. This could direct a new focus for better and more specific therapeutic treatments based on immuno-intervention that can promise a better quality of life for those suffering from chronic disturbances of the immune response.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Manipulation of innate immunity by bacterial pathogens.

The past decade has witnessed tremendous growth in two related fields: innate immunity and microbial pathogenesis. Many pathogens have evolved mechanisms to infect their hosts in the face of a fully functional innate immune system, and there are numerous examples by which pathogens avoid recognition and/or suppress inflammation. In this review, I suggest that pathogens not only survive the innate immune response, but use it to promote their pathogenesis.

Animals↗

PubMed2003

The dual role of LBP and CD14 in response to Gram-negative bacteria or Gram-negative compounds.

Innate immunity initiates protection of the host organism against invasion of micro-organisms by specific recognition mechanisms. This article reviews the dual role of LBP/CD14 in innate immunity, focusing mostly on experiments performed in mice by the authors. LPS induces uncontrolled pro-inflammatory response that kills the host and is LBP- and CD14-dependent, as neutralization of LBP and CD14 prevents lethal shock. However, surprisingly, the synthetic Pam3CysSerLys4 bacterial lipoprotein from Escherichia coli (BLP), which is well tolerated in mice, kills the mice upon LBP or CD14 blockade. Furthermore, after blockade of LBP and CD14, the mice succumb to a challenge with virulent Klebsiella pneumoniae or Salmonella typhimurium. Therefore, host responses to Gram-negative bacteria are not identical to that of LPS or BLP. When the host is in the presence of virulent Gram-negative bacteria, the invading pathogens must be held in check by the innate immune system until a specific immune response is mounted. Under these conditions, LBP, CD14, and likely Toll-like receptors (TLRs) are a prerequisite to trigger a pro-inflammatory response of macrophages, which is crucial for keeping an infection under control. These studies indicate that we are very far from understanding how the innate system works and more work needs to be done concerning LBP, CD14 or TLRs. Therefore, caution should be the rule about the use of therapeutic approaches to block the pro-inflammatory response in Gram-negative infections.

Animals↗

PubMed2002

The CD1 family and T cell recognition of lipid antigens.

For many years it was thought that T lymphocytes recognized only peptide antigens presented by MHC class I or class II molecules. Recently, it has become clear that a wide variety of lipids and glycolipids are also targets of the T cell response. This novel form of cell-mediated immune recognition is mediated by a family of lipid binding and presenting molecules known as CD1. The CD1 proteins represent a small to moderate sized family of beta2-microglobulin-associated transmembrane proteins that are distantly related to MHC class I and class II molecules. They are conserved in most or all mammals, and control the development and function of T cell populations that participate in innate and adaptive immune responses through the recognition of self and foreign lipid antigens. Here we review the current state of our understanding of the structure and function of CD1 proteins, and the role of CD1-restricted T cell responses in the immune system.

Animals↗

PubMed2006

Selective regulation of IL-10 signaling and function by zymosan.

Balanced activity of pro- and anti-inflammatory cytokines during innate immune responses is required to allow effective host defense while avoiding tissue damage and autoimmunity. Induction of cytokine production after recognition of pathogen-associated molecular patterns (PAMPs) by innate immune cells has been well demonstrated, but modulation of cytokine function by PAMPs is not well understood. In this study we show that stimulation of macrophages with zymosan, which contains PAMPs derived from yeast, rapidly extinguished macrophage responses to IL-10, a suppressive cytokine that limits inflammatory tissue damage but also compromises host defense. The mechanism of inhibition involved protein kinase Cbeta and internalization of IL-10R, and was independent of TLR2 and phagocytosis. Inhibition of IL-10 signaling and function required direct contact with zymosan, and cells in an inflammatory environment that had not contacted zymosan remained responsive to the paracrine activity of zymosan-induced IL-10. These results reveal a mechanism that regulates IL-10 function such that antimicrobial functions of infected macrophages are not suppressed, but the activation of surrounding noninfected cells and subsequent tissue damage are limited. The fate of individual cells in an inflammatory microenvironment is thus specified by dynamic interactions among host cells, microbes, and cytokines that determine the balance between protection and pathology.

Animals↗

PubMed2006

Structure and function of the long pentraxin PTX3 glycosidic moiety: fine-tuning of the interaction with C1q and complement activation.

The prototypic long pentraxin PTX3 is a unique fluid-phase pattern recognition receptor that plays a nonredundant role in innate immunity and female fertility. The PTX3 C-terminal domain is required for C1q recognition and complement activation and contains a single N-glycosylation site on Asn 220. In the present study, we characterized the structure of the human PTX3 glycosidic moiety and investigated its relevance in C1q interaction and activation of the complement classical pathway. By specific endo and exoglycosidases digestion and direct mass spectrometric analysis, we found that both recombinant and naturally occurring PTX3 were N-linked to fucosylated and sialylated complex-type sugars. Interestingly, glycans showed heterogeneity mainly in the relative amount of bi, tri, and tetrantennary structures depending on the cell type and inflammatory stimulus. Enzymatic removal of sialic acid or the entire glycosidic moiety equally enhanced PTX3 binding to C1q compared to that in the native protein, thus indicating that glycosylation substantially contributes to modulate PTX3/C1q interaction and that sialic acid is the main determinant of this contribution. BIAcore kinetic measurements returned decreasing K(off) values as sugars were removed, pointing to a stabilization of the PTX3/C1q complex. No major rearrangement of PTX3 quaternary structure was observed after desialylation or deglycosylation as established by size exclusion chromatography. Consistent with C1q binding, PTX3 desialylation enhanced the activation of the classical complement pathway, as assessed by C4 and C3 deposition. In conclusion, our results provided evidence of an involvement of the PTX3 sugar moiety in C1q recognition and complement activation.

Animals↗

PubMed2000

A horseshoe crab receptor structurally related to Drosophila Toll.

Innate immunity against microbial pathogens relies on the pattern recognition of cell wall components on invading microbes. Recent evidence has shown that a mammalian Toll-like receptor (TLR) is activated by bacterial lipopolysaccharides (LPS). The innate immunity in invertebrates is also triggered by LPS, as seen in the hemolymph coagulation in horseshoe crab. We report the cloning of a TLR from the Japanese horseshoe crab Tachypleus tridentatus. A cDNA coding for Tachypleus Toll was isolated from a hemocyte cDNA library and the open reading frame codes for a proprotein including a signal sequence. Like Drosophila Toll, Tachypleus Toll is a type I transmembrane protein with an extracellular domain consisting of two leucine-rich repeats flanked by two cystein-rich clusters and a cytoplasmic domain exhibiting striking similarity with the cytoplasmic domain of interleukin-1 receptor. Tachypleus Toll is most similar to Drosophila Toll in the domain architecture and the overall length.

Animals↗

PubMed2002

Recognition of lipopeptides by Toll-like receptors.

Toll-like receptors (TLRs) recognize specific molecular patterns present only in micro-organisms and thereby activate innate immune cells. TLR2 is essential for the recognition of peptidoglycan and lipoprotein/lipopeptides. Lipoprotein/lipopeptides are observed in cell walls of a variety of micro-organisms. Host immune cells recognize the specific patterns of lipoprotein/lipopeptides through the association of TLR2 with other TLRs. TLR1 and TLR6 are highly homologous to TLR2 in structure. TLR6-deficient mice showed an impaired response to mycoplasmal lipopeptides that are diacylated, whereas TLR1-deficient mice were defective in their response to bacterial lipopeptides that are triacylated. TLR2-deficient mice did not show any inflammatory response to either type of lipopeptide. The functional association of TLR2 with TLR1 or TLR6 has been demonstrated. Thus, TLR1 and TLR6 are involved in the discrimination of a subtle difference between triacyl and diacyl lipopeptides through interaction with TLR2.

Animals↗

PubMed2005

Prion protein: a pattern recognition receptor for viral components and uric acid responsible for the induction of innate and adaptive immunity.

Prion protein, known as Prp(c), is a GPI-anchored membrane bound glycoprotein ubiquitously expressed in the body. To date, the precise nature of its physiological role remains a mystery. The prion protein's presence on neurons and immune effector cells suggests a dual neurological and immunological function. Some consensus exists regarding the proposed involvement of Prp(c) in neurodevelopment, where it would serve to mediate interactions between the extra-cellular matrix (ECM) and the neuron. There is also evidence that Prp plays a part in immunity, although the exact nature of the role remains unclear. Interestingly, a role in both immunity and development is a functional division seen in other types of receptors, most notably the Toll Receptor. In mammals, toll-like receptors (TLRs) are partly responsible for both innate and adaptive immune activity. However, recently several TLR independent pathways have been identified that initiate such responses. Unfortunately, receptors for such pathways remain unidentified. But based upon its functional homology to Toll Receptors, its known interactions with several viruses, and its possible downstream effector proteins, it is proposed that Prp(c) represents a new type of pattern recognition receptor responsible for TLR-independent induction of myeloid dendritic cell and macrophage maturation and later T-cell activation. From what is known of the ligands for the prion protein, it is proposed that this response would be initiated via the binding of uric acid, viral RNA, or viral structural proteins to Prp(c). It will further be proposed that Prp(c)'s ability to interact with viral components stems from its evolutionary origin as a horizontally transferred gene from an early RNA virus. Finally, Prp(c)'s functional role in immunity will be related to the pathophysiology of TSEs, with observations made concerning immune response to infection and agent composition.

Animals↗

PubMed2005

Enhanced resistance to Gram-positive bacterium and increased susceptibility to bacterial endotoxin in mice sensitized with Propionibacterium acnes: involvement of Toll-like receptor.

Mice sensitized with Propionibacterium acnes showed an enhanced resistance against infection with Listeria monocytogenes in contrast to the increased susceptibility to LPS-induced endotoxin shock. The enhanced protection to L. monocytogenes was mediated by activated innate immunity but not by generation of Listeria-specific acquired immunity. After infection with L. monocytogenes, the elimination of bacteria was observed earlier in accordance with a higher level of endogenous cytokine production in P. acnes-sensitized mice than in control mice. Peritoneal cells from P. acnes-sensitized mice produced a larger amount of IL-12p70 and nitric oxide after stimulation with heat-killed L. monocytogenes or peptidoglycan purified from Staphylococcus aureus. RT-PCR analysis showed that the expression of TLR2 but not TLR1, TLR4 nor TLR6 was induced by injection of P. acnes in peritoneal cells. These results indicated that P. acnes-sensitization could induce the activation of innate immunity against L. monocytogenes through increased recognition of bacterial components by TLR2.

Animals↗

PubMed2006

The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses.

Multiple sclerosis-associated retroviral element (MSRV) is a retroviral element, the sequence of which served to define the W family of human endogenous retroviruses. MSRV viral particles display proinflammatory activities both in vitro in human mononuclear cell cultures and in vivo in a humanized SCID mice model. To understand the molecular basis of such properties, we have investigated the inflammatory potential of the surface unit of the MSRV envelope protein (ENV-SU), the fraction that is poised to naturally interact with host cells. We report in this study that MSRV ENV-SU induces, in a specific manner, human monocytes to produce major proinflammatory cytokines through engagement of CD14 and TLR4, which are pattern recognition receptors of primary importance in innate immunity. ENV-SU could also trigger a maturation process in human dendritic cells. Finally, ENV-SU endowed dendritic cells with the capacity to support a Th1-like type of Th cell differentiation. The data are discussed in the context of immune responses and chronic proinflammatory disorders.

Amino Acid Sequence↗